The circulatory system represents an extensive, branching, network of blood vessels which is essential for the supply of oxygen and nutrients to tissues and for the removal of byproducts of metabolism. In adults the development of new blood vessels or "angiogenesis" rarely occurs except during wound healing or as a result of a number of pathological situations termed "angiogenesis-dependent diseases".sup.(1,2). The most important of these is the angiogenesis associated with the growth of solid tumours and with proliferative retinopathies. Angiogenesis may also play an important role in rheumatoid arthritis and psoriasis.
Angiogenesis inhibitors can, therefore, be of considerable value in the treatment of angiogenesis-dependent diseases. For example, in the case of solid tumours, the development of a blood supply is essential for the growth and survival of the tumour. Thus, inhibition of angiogenesis can provide a highly selective means of inducing tumour regression. Similarly, angiogenesis inhibitors may be used to prevent the blindness associated with proliferative diabetic retinopathy, one of the major complications of diabetes.
In work leading to the present invention, monoclonal antibodies (mAbs) have been developed against proliferating/angiogenic human endothelial cells which can be used either to directly inhibit angiogenesis or to target cytotoxic drugs or radioisotope labels to sites of angiogenesis. Since angiogenesis does not occur in adults, except following tissue injury, such mAbs can be remarkably specific. Furthermore, unlike other lines of research which have produced cancer cell-specific mAbs to target cytotoxic drugs to tumours, the present invention is directed to producing mAbs against host antigens. This approach has the major advantage that generation of "resistant" variants of the tumour cannot occur and, in theory, one mAb could be used to treat all solid tumours. An additional advantage is that endothelial cells, by virtue of their vascular location, are very accessible to mAbs in the circulation.